Metastatic Breast Adenocarcinoma Research Articles

A Petiveria alliacea standardized fraction induces breast adenocarcinoma cell death by modulating glycolytic metabolism

Ethnopharmacological relevanceFolk medicine uses aqueous and alcoholic extracts from Petiveria alliacea (Phytolaccaceae) in leukemia and breast cancer treatment in the Caribbean, Central and South America. Herein, we validated the biological activity of a Petiveria alliacea fraction using a metastatic breast adenocarcinoma model (4T1). Materials and methodsPetiveria alliacea fraction biological activity was determined estimating cell proliferation, cell colony growth capacity and apoptosis (caspase-3 activity, DNA fragmentation and mitochondrial membrane potential) in 4T1 cells. Petiveria alliacea was used at IC50 concentration (29 µg/mL) and 2 dilutions below, doxorubicin at 0.27 µg/mL (positive control) and dibenzyl disulfide at 2.93 µg/mL (IC50 fraction marker compound). Proteomic estimations were analyzed by LC–MS–MS. Protein level expression was confirmed by RT-PCR. Glucose and lactate levels were measured by enzymatic assays. LD50 was established in BALB/c mice and antitumoral activity evaluated in mice transplanted with GFP-tagged 4T1 cells. Mice were treated with Petiveria alliacea fraction via I.P (182mg/kg corresponding to 1/8 of LD50 and 2 dilutions below). ResultsPetiveria alliacea fraction in vitro induces 4T1 cells apoptosis, caspase-3 activation, DNA fragmentation without mitochondria membrane depolarization, and decreases cell colony growth capacity. Also, changes in glycolytic enzymes expression cause a decrease in glucose uptake and lactate production. Fraction also promotes breast primary tumor regression in BALB/c mice transplanted with GFP-tagged 4T1 cells. ConclusionA fraction of Petiveria alliacea leaves and stems induces in vitro cell death and in vivo tumor regression in a murine breast cancer model. Our results validate in partly, the traditional use of Petiveria alliacea in breast cancer treatment, revealing a new way of envisioning Petiveria alliacea biological activity. The fraction effect on the glycolytic pathway enzymes contributes to explain the antiproliferative and antitumor activities.

Metastatic Spinal Cord Compression (MSCC) —The Evolving Story from Kashmir

Aim: To know the demographics of the patients most commonly involved by metastatic cord compression in Kashmir and to find the commonest primary organ to metastasize to spine causing cord compression. Methods: A hospital-based 10-year retro-prospective study was carried out in the Department of Neurosurgery of Sher-i-Kashmir Institute of Medical Sciences, Soura from July 2002 to June 2012, which is the premier tertiary care institute of the Kashmir valley. Patients were evaluated for metastatic spinal cord compression based on a standard proforma and specialized investigations were carried out and were deemed necessary by the concerned neurosurgical unit. Results: The commonest primary malignancy to metastasize to the spinal column in our study was Non-Hodgkin’s lymphoma, followed in turn by metastatic squamous cell carcinoma lung, metastatic intraductal carcinoma breast and metastatic adenocarcinoma prostate. Predominantly dorsal spine was the commonest region of spine involved by MSCC. Conclusion: Metastatic spinal cord compression is coming up in a big way. As the long-term cancer survivors increase due to multi-modality treatment protocols aimed at treating cancers and prolonging survival, there will be a proportionate increase in the number of patients who will potentially land up in metastatic spinal cord compression.

Cutaneous metastatic breast adenocarcinoma twenty years post-mastectomy: A lesson to learn

Introduction: cutaneous metastasis complicating solid organ malignancy is a common clinical entity, and the primary is often metastatic breast cancer. skin metastasis from breast cancer occurs in about 25% of breast cancer patients. case report: We present a case report of a patient with a history of modified left radical mastectomy and chemotherapy for breast cancer twenty years earlier, who presented for surgical evaluation of multiple painful skin lesions. Initial punch biopsy of skin lesions reported negative for malignancy. s urgical biopsy provided tissue which demonstrated a rare histopathological morphology for cutaneous metastatic breast adenocarcinoma. conclusion: this report makes the case for considering surgical biopsy when conventional biopsy reports negative for malignancy, especially in the setting of remote or recent cancer history. It also advises prolonged relapse surveillance, well beyond the current protocol, as well as development of prognostic markers for identifying patients at risk of long disease latency after primary treatment.

Synchronous antiresorptive osteonecrosis of the jaws and breast cancer metastasis

Antiresorptive osteonecrosis of the jaws (ARONJ) is a significant and poorly understood oral complication that may affect patients receiving antiresorptive agents, such as intravenous bisphosphonate therapy. There are scarce reports of the coexistence of ARONJ and metastasis at the same jaw site in the English-language literature. In the present case, a 60-year-old white woman was referred for the evaluation of a nonhealing extraction socket. The patient was undergoing treatment with intravenous zoledronic acid to metastatic breast cancer in bone, and her medical history and clinical characteristics led to the diagnosis of ARONJ. Nevertheless, histologic analysis showed a fragment of necrotic bone and bacterial colonies associated with malignant epithelial cells that were confirmed to be metastatic breast adenocarcinoma. This case showed that jaw metastasis can occur at the same time and site of ARONJ, making diagnosis and management challenging.

Breast Metastases to Thyroid Gland

Metastases to the thyroid gland are uncommon. We present the sonographic features of metastatic breast adenocarcinoma to the thyroid in a 67-year-old woman. The lesion measured up to 0.9 cm in diameter, contained an echogenic focus with associated ring-down, and was predominantly cystic, thereby resembling a benign nodule. Because of the patient's history of breast adenocarcinoma, the nodule nevertheless underwent fine-needle aspiration. The unusual appearance of the thyroid nodule underscores the importance of considering patient history in deciding whether obtaining tissue diagnosis of thyroid nodules is warranted.

Secoemestrin D, a Cytotoxic Epitetrathiodioxopiperizine, and Emericellenes A–E, Five Sesterterpenoids from Emericella sp. AST0036, a Fungal Endophyte of Astragalus lentiginosus1

A new epitetrathiodioxopiperizine, secoemestrin D (1), and five sesterterpenoids bearing a new carbon skeleton, emericellenes A-E (2-6), together with previously known fungal metabolites, sterigmatocystin (7), arugosin C (8), and epiisoshamixanthone (9), were obtained from the endophytic fungal strain Emericella sp. AST0036 isolated from a healthy leaf tissue of Astragalus lentiginosus. The planar structures and relative configurations of the new metabolites 1-6 were elucidated using MS and 1D and 2D NMR spectroscopic data. All compounds were evaluated for their potential anticancer activity using a panel of six tumor cell lines and normal human fibroblast cells. Only metabolites 1 and 7 showed cytotoxic activity. More importantly, secoemestrin D (1) exhibited significant cytotoxicity with IC50 values ranging from 0.06 to 0.24 μM and moderate selectivity to human glioma (SF-268) and metastatic breast adenocarcinoma (MDA-MB-231) cell lines.

Synthesis and anticancer activity of aminodihydroquinoline analogs: Identification of novel proapoptotic agents

A series of 2-aminodihydroquinoline analogs were synthesized and their in vitro cytotoxicities against metastatic breast adenocarcinoma cell line MDA-MB-231 were tested. Five out of 16 compounds exhibited promising activity and structure–activity relationship revealed major role of dialkylaminoethyl substituents on dihydroquinoline ring for the activity. Two compounds, 5f and 5h, presented cytotoxicity with IC50 values of about 2μM when the compounds were treated to the cells without serum. The cell proliferation was inhibited mildly when the cells cultured with serum. Flow cytometry analyses showed that those compounds arrested the cells at G2/M checkpoint when the cell cycle is active while they induce apoptosis when the cell growth is restricted due to the absence of growth factors. These results suggest the two novel compounds may have anticancer activity through cell cycle arrest and pro apoptosis mechanism.

A novel animal model of human breast cancer metastasis to the spine: a pilot study using intracardiac injection and luciferase-expressing cells

ObjectMetastatic spine disease is prevalent in cancer victims; 10%–30% of the 1.2 million new patients diagnosed with cancer in the US exhibit spinal metastases. Unfortunately, treatments are limited for these patients, as disseminated disease is often refractory to chemotherapy and is difficult to treat with surgical intervention alone. New animal models that accurately recapitulate the human disease process are needed to study the behavior of metastases in real time.MethodsIn this study the authors report on a cell line that reliably generates bony metastases following intracardiac injection and can be tracked in real time using optical bioluminescence imaging. This line, RBC3, was derived from a metastatic breast adenocarcinoma lesion arising in the osseous spine of a rat following intracardiac injection of MDA-231 human breast cancer cells.ResultsUpon culture and reinjection of RBC3, a statistically significantly increased systemic burden of metastatic tumor was noted. The resultant spine lesions were osteolytic, as demonstrated by small animal CT scanning.ConclusionsThis cell line generates spinal metastases that can be tracked in real time and may serve as a useful tool in the study of metastatic disease in the spine.

Elucidating mechanical transition effects of invading cancer cells with a subnucleus-scaled microfluidic serial dimensional modulation device.

Mechanical boundaries that define and regulate biological processes, such as cell-cell junctions and dense extracellular matrix networks, exist throughout the physiological landscape. During metastasis, cancer cells are able to invade across these barriers and spread to distant tissues. While transgressing boundaries is a necessary step for distal colonies to form, little is known about interface effects on cell behavior during invasion. Here we introduce a device and metric to assess cell transition effects across mechanical barriers. Using MDA-MB-231 cells, a highly metastatic breast adenocarcinoma cell line, our results demonstrate that dimensional modulation in confined spaces with mechanical barriers smaller than the cell nucleus can induce distinct invasion phases and elongated morphological states. Further investigations on the impact of microtubule stabilization and drug resistance reveal that taxol-treated cells have reduced ability in invading across tight spaces and lose their super-diffusive migratory state and taxol-resistant cells exhibit asymmetric cell division at barrier interfaces. These results illustrate that subnucleus-scaled confinement modulation can play a distinctive role in inducing behavioral responses in invading cells and can help reveal the mechanical elements of non-proteolytic invasion.

An Antitubulin Agent BCFMT Inhibits Proliferation of Cancer Cells and Induces Cell Death by Inhibiting Microtubule Dynamics

Using cell based screening assay, we identified a novel anti-tubulin agent (Z)-5-((5-(4-bromo-3-chlorophenyl)furan-2-yl)methylene)-2-thioxothiazolidin-4-one (BCFMT) that inhibited proliferation of human cervical carcinoma (HeLa) (IC50, 7.2±1.8 µM), human breast adenocarcinoma (MCF-7) (IC50, 10.0±0.5 µM), highly metastatic breast adenocarcinoma (MDA-MB-231) (IC50, 6.0±1 µM), cisplatin-resistant human ovarian carcinoma (A2780-cis) (IC50, 5.8±0.3 µM) and multi-drug resistant mouse mammary tumor (EMT6/AR1) (IC50, 6.5±1µM) cells. Using several complimentary strategies, BCFMT was found to inhibit cancer cell proliferation at G2/M phase of the cell cycle apparently by targeting microtubules. In addition, BCFMT strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. At its half maximal proliferation inhibitory concentration (10 µM), BCFMT reduced the rates of growing and shortening phases of microtubules in MCF-7 cells by 37 and 40%, respectively. Further, it increased the time microtubules spent in the pause (neither growing nor shortening detectably) state by 135% and reduced the dynamicity (dimer exchange per unit time) of microtubules by 70%. In vitro, BCFMT bound to tubulin with a dissociation constant of 8.3±1.8 µM, inhibited tubulin assembly and suppressed GTPase activity of microtubules. BCFMT competitively inhibited the binding of BODIPY FL-vinblastine to tubulin with an inhibitory concentration (Ki) of 5.2±1.5 µM suggesting that it binds to tubulin at the vinblastine site. In cultured cells, BCFMT-treatment depolymerized interphase microtubules, perturbed the spindle organization and accumulated checkpoint proteins (BubR1 and Mad2) at the kinetochores. BCFMT-treated MCF-7 cells showed enhanced nuclear accumulation of p53 and its downstream p21, which consequently activated apoptosis in these cells. The results suggested that BCFMT inhibits proliferation of several types of cancer cells including drug resistance cells by suppressing microtubule dynamics and indicated that the compound may have chemotherapeutic potential.

Transducer of Cdc42-dependent actin assembly promotes breast cancer invasion and metastasis

Metastatic breast adenocarcinomas display activation signatures for signaling pathways that trigger cell motility and tissue invasion. Here, we report that the adaptor protein transducer of Cdc42-dependent actin assembly-1 (Toca-1) is expressed in highly invasive breast cancers and regulates their metastatic phenotypes. We show that Toca-1 localizes to the filamentous actin-rich core of invadopodial protrusions actively degrading the extracellular matrix (ECM). Toca-1 colocalizes with Cortactin, and we show that this interaction is mediated by the SH3 domain of Toca-1. Stable knockdown (KD) of Toca-1 expression in MDA-MB-231 cells led to a significant defect in epidermal growth factor (EGF)-induced cell migration and invasion. Toca-1 KD cells also showed significant defects in EGF- and Src-induced ECM digestion and formation of invadopodial membrane protrusions. To test the role of Toca-1 in metastasis, we achieved stable Toca-1 KD in both human and rat metastatic breast adenocarcinoma cell lines. Orthotopic tumor xenografting of control and Toca-1 KD cells in natural-killer /B-/T-cell-deficient mice revealed a significant defect in spontaneous lung metastases with Toca-1 silencing in vivo. In contrast, no defects in primary tumor growth or lung seeding following tail vein injection of Toca-1 KD cells was observed, suggesting that Toca-1 functions at an early step in the dissemination of metastatic breast tumor cells. Taken together, our results identify Toca-1 as a proinvasive protein in breast adenocarcinoma and a potential therapeutic target to limit tumor metastasis.

VH15 Percutaneous Cholecystoscopy to Diagnose Metastatic Breast Adenocarcinoma

61 year old female with a remote history of breast cancer was found to have extensive fibrotic tissue involving the anterior mediastinum and abdomen during attempted cholecystectomy. Cholecystectomy was aborted and a cholecystostomy tube was placed. The lesion encased the antrum of the stomach, duodenum, common bile duct, head of the pancreas, and gallbladder. Endoscopic ultrasound with mucosal biopsies and FNA was performed twice revealing only fibrotic tissue. Mediastinoscopy with excisional biopsy revealed metastatic breast adenocarcinoma. Despite chemotherapy, there continued to be persistent cystic duct obstruction requiring continuation of the cholecystostomy tube and duodenal obstruction requiring duodenal stent placement and palliative gastrojejunostomy. The etiology of the abdominal process was unclear and her oncologists requested additional diagnostic studies. Due to prior duodenal stent placement and gastrojejunostomy, we attempt percutaneous cholecystoscopy.

Mandibular metastases as first clinical sign of an occult male breast cancer

A 73-year-old man presented with a painful swelling of the left temporomandibular joint with no other symptoms. Panoramic radiography showed an osteolytic lesion in the left mandibular body, while magnetic resonance imaging provided the most accurate view of an osteolytic lesion in the left condyle. Skeletal scintigraphy showed increased uptake in the mandibular anatomical area. A diagnosis of metastatic breast adenocarcinoma was made from mandibular biopsies which proved to be ductal carcinoma, with no evidence of any other metastases. Clinicopathologic features of this case are reviewed.

Smardaesidins A-G, isopimarane and 20-nor-isopimarane diterpenoids from Smardaea sp., a fungal endophyte of the moss Ceratodon purpureus.

Five new isopimarane diterpenes, smardaesidins A-E (1- 5) and two new 20-nor-isopimarane diterpenes, smardaesidins F (6) and G (7), together with sphaeropsidins A (8) and C-F (10-13) were isolated from an endophytic fungal strain, Smardaea sp. AZ0432, occurring in living photosynthetic tissue of the moss Ceratodon purpureus . Of these, smardaesidins B (2) and C (3) were obtained as an inseparable mixture of isomers. Chemical reduction of sphaeropsidin A (8) afforded sphaeropsidin B (9), whereas catalytic hydrogenation of 8 yielded 7-O-15,16-tetrahydrosphaeropsidin A (14) and its new derivative, 7-hydroxy-6-oxoisopimara-7-en-20-oic acid (15). The acetylation and diazomethane reaction of sphaeropsidin A (8) afforded two of its known derivatives, 6-O-acetylsphaeropsidin A (16) and 8,14-methylenesphaeropsidin A methyl ester (17), respectively. Methylation of 10 yielded sphaeropsidin C methyl ester (18). The planar structures and relative configurations of the new compounds 1-7 and 15 were elucidated using MS and 1D and 2D NMR experiments, while the absolute configurations of the stereocenters of 4 and 6-8 were assigned using a modified Mosher's ester method, CD spectra, and comparison of specific rotation data with literature values. Compounds 1-18 were evaluated for their potential anticancer activity using several cancer cell lines and cells derived from normal human primary fibroblasts. Of these, compounds 8, 11, and 16 showed significant cytotoxic activity. More importantly, sphaeropsidin A (8) showed cell-type selectivity in the cytotoxicity assay and inhibited migration of metastatic breast adenocarcinoma (MDA-MB-231) cells at subcytotoxic concentrations.

Endobronchial metastatic breast cancer with pagetoid histology mimicking bronchial pagetoid squamous cell carcinoma in situ

We report a case of a 56-year-old woman with endobronchial breast cancer metastasis of unusual histology. The patient presented with persistent cough, and a lesion was noted in the left mainstem bronchus on bronchoscopic examination. Biopsy revealed extensive squamous metaplasia of bronchial epithelium along with large, atypical cells exhibiting pagetoid intraepithelial spread within squamous mucosa. Immunohistochemical stains were compatible with a diagnosis of metastatic breast adenocarcinoma with pagetoid spread. To our knowledge, this is the first reported case of endobronchial breast cancer metastasis with this histologic presentation. In this report, we describe the clinical, radiographic, bronchoscopic, histologic, and immunohistochemical characteristics of this case. We provide a brief review of existing literature on endobronchial breast cancer metastasis. In addition, we discuss the principal differential diagnosis of bronchial pagetoid lesions. This report raises awareness of this uncommon manifestation of metastatic breast cancer.

Simultaneous forequarter amputation and radical mastectomy for metastatic breast carcinoma in a male patient: a case report

Although the majority of forequarter amputations are performed for high-grade bone and soft tissue sarcomas or extensive osteomyelitis of the upper extremity, this radical operation may also be indicated for the curative treatment of recurrent breast cancer and for the palliation of locally advanced breast cancer. We report a male patient with metastatic breast adenocarcinoma who underwent simultaneous mastectomy and forequarter amputation for the management of both his primary and metastatic disease.

Metastatic lobular breast adenocarcinoma presenting as cauda equina syndrome

Metastatic lobular breast adenocarcinoma presenting as cauda equina syndrome

Metastatic adenocarcinoma of breast within a benign melanocytic nevus in the context of cutaneous breast metastatic disease

Metastatic breast cancer of skin may be seen in a number of forms. It is rare to find it in association with a benign melanocytic nevus. We describe a patient with metastatic adenocarcinoma of breast within a benign melanocytic nevus and delineate this occurrence within the context of reviewing cutaneous breast metastatic disease.

Traitement endovasculaire du syndrome cave supérieur d’origine néoplasique : à propos de 34 patients

To report our experience with the treatment of 34 patients with SVC syndrome from neoplastic origin using the Wallstent. Thirty-four patients were treated between January 2000 and February 2007: 21 males and 13 females, aged 44-81 years, with non-small-cell lung carcinoma in 27 cases (79%), small-cell lung carcinoma in 5 cases (15%) and metastatic breast adenocarcinoma to the mediastinum in 2 cases (6%). All patients were treated using the stainless steel self-expanding Wallstent. A dual brachial-femoral access was used in all cases. Stent placement was possible in all cases. Per procedure acute respiratory distress occurred in 2 cases: 1 case of acute pulmonary edema and 1 case of tamponade. Symptoms resolved within 24 hours. Twenty-six patients died from disease progression, 8 during the first month, and 16 within 32-545 days post-procedure (mean: 213.4 days). Five patients with recurrent SVC syndrome underwent repeat treatment (restenosis in 3 cases, fracture in 1 case, thrombosis in 1 case), for primary and secondary patency rates of 81% and 100%. Palliative stent treatment of neoplastic SVC syndrome is reliable, safe and provides long-standing improvement in quality of life.

Phase I Dose Escalation Study With Irinotecan, Capecitabine, Epirubicin, and Granulocyte Colony-Stimulating Factor Support for Patients With Solid Malignancies

Preclinical studies using sequences of topoisomerase I and II inhibitors suggested synergism; preliminary clinical studies, resulting in enhanced antitumor responses, confirm this in selected malignancies. This study determined the maximum-tolerated dose (MTD), toxicity, and pharmacokinetics of irinotecan (CPT-11), capecitabine, and epirubicin in patients with metastatic adenocarcinoma of lung, breast, or gastrointestinal tract. Correlation of topoisomerase IIbeta was also done. Eligibility criteria included the following: documented adenocarcinoma of the lung, breast, or gastrointestinal tract, <3 prior chemotherapy regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, age > or =18 years, adequate organ function, and signed informed consent. Irinotecan was administered at 250 mg/m2 intravenously day 1 every 21-day cycle, but was reduced to 180 mg/m2 in cohort 2 due to toxicity. Capecitabine was administered at 750 mg/m2 twice daily days 2 to 14 in cohort 1 but only on days 2 to 7 from cohort 2 due to early neutropenia and to allow for prophylactic granulocyte colony-stimulating factor (GCSF) support. Epirubicin was administered at 40 mg/m2 in cohort 1, but reduced to 30 mg/m2 in cohort 2, then reescalated until the MTD was reached. Toxicity was assessed in 21 patients; response was assessed in 17 patients. The most common grade 3 to 4 toxicities included neutropenia (57.1%) and anemia (28.6%). The MTD of epirubicin was 50 mg/m2. In evaluable patients, there were 2 partial responses (11.8%) and 13 stable disease (76.5%); these correlated well with topoisomerase IIbeta. The recommended doses for phase II studies: irinotecan 180 mg/m2 day 1, epirubicin 50 mg/m2 day 2, and capecitabine 750 mg/m2 twice daily days 2 to 7 of each 21-day cycle. This combination is reasonably active and warrants evaluation in the phase II setting.